Method and device for enhancing memory consolidation

ABSTRACT

The present invention relates to methods and devices to consolidate memory and/or cognitive functions by monitoring brain rhythms and delivering a stimulus at an appropriate stage of sleep cycle.

FIELD OF INVENTION

The present invention relates to methods and devices to consolidatememory and/or cognitive functions by monitoring brain rhythms anddelivering a stimulus at an appropriate stage of sleep cycle.

BACKGROUND OF INVENTION

Strategies to alleviate or mitigate cognitive deficits withpharmaceutical, educational, and behavioral interventions have receivedsignificant attention recently. New methods for improving the lives ofthose with intellectual disabilities, age-related cognitive decline, andother forms of learning disability by reinforcing and/or consolidatingmemory and cognitive function are desired. Moreover, healthy,typically-developed students of all ages would benefit from a method forenhancing memory consolidation and thus long-term memory retention.

Sleep has many inherent benefits, including an important role in memoryconsolidation. Brain rhythms regulate information processing indifferent states to enable learning and memory formation.

The sleep begins with light sleep (stage I and stage II) which leadsquickly to slow-wave sleep (SWS) state (stages 3 and 4). After about 90minutes, rapid eye movement (REM) sleep appears. These stages are thefirst sleep cycle. A cycle lasts about 90 minutes. One night has 4 to 6cycles, depending on the duration of sleep. The first half of sleep isparticularly rich in deep sleep, while the second half is essentiallyconstituted by alternating light sleep and REM sleep.

SWS is thought to be critical for many of sleep's restorative effects(Cirelli C, Tononi G 2008 PLoS Biol 6(8): e216). In particular, manyconvergent experimental findings suggest that sleep slow oscillations(SO, <1 Hz) in the electroencephalogram (EEG), characterized by globalup-states (neuronal firing) and down-states (neuronal silence), canpromote synaptic downscaling and plasticity and, consequently, may playan active role in learning and memory consolidation (Steriade M, et al1993 Science 262(5134):679-85; Tononi, G and Cirelli, C 2006 Sleep Med.Rev. 10, 49-62). In this context, stimuli, in addition to induceevoked-potentials, can affect EEG activity by boosting various sleepbrain rhythms and, thus, could provide a tool to artificially improve SOgeneration (Tononi, G., et al 2010 Medicamundi 54, 73-79). Nevertheless,previous studies imposed simulations on the brain disregarding the phaseof ongoing endogenous oscillating activity, which might explain theoverall limited enhancement in SO induction (patent applications:WO2012/138761, WO2014/028372).

In addition, a precedent study already tried to stimulate in phase withSO but no increase in SO events was observed nor differences in sleeparchitecture (Ngo H V, et al. 2013 Neuron 78, 545-553).

Surprisingly, the new method disclosed herein is able to initiate andenhance SO by presenting stimuli (tones, lights, tactile stimulation onthe body surface) in synchrony with the brain's own rhythm. Moresurprisingly the sleep architecture of the subject is modified.

SUMMARY

One object of the present invention relates to a non-invasive method forenhancing and/or consolidating memory in a subject in need thereofcomprising:

-   -   a. monitoring a subject's sleeping cycle,    -   b. detecting the end of stage I of a non-REM light sleep state,    -   c. applying a first stimulus on said subject at the onset of        stage II of a non-REM light sleep state,    -   d. applying a second stimulus on said subject,    -   e. repeating applying the first stimulus and the second stimulus        until the end of stage IV, and    -   f. restarting said method at step c when an onset of a further        stage II is detected, thereby extending slow wave sleep stages        and modulating the sleep architecture of said subject.

Another object of the present invention relates to a non-invasive methodfor enhancing and/or consolidating memory comprising:

-   -   a. monitoring sleeping cycle,    -   b. detecting the end of stage I of a non-REM light sleep state,    -   c. emitting a first stimulus at the onset of stage II of a        non-REM light sleep state,    -   d. emitting a second stimulus,    -   e. repeating applying the first stimulus and the second stimulus        until the end of stage IV, and    -   f. restarting said method at step c. when an onset of a further        stage II is detected, thereby extending slow wave sleep stages        and modulating the sleep architecture.

The present application also relates to a non-invasive method formodulating sleep architecture comprising:

-   -   a. monitoring sleeping cycle,    -   b. detecting the end of stage I of a non-REM light sleep state,    -   c. emitting a first stimulus at the onset of stage II of a        non-REM light sleep state,    -   d. emitting a second stimulus,    -   e. repeating applying the first stimulus and the second stimulus        until the end of stage IV, and    -   f. restarting said method at step c. when an onset of a further        stage II is detected,

thereby improving memory consolidation and/or cognition and/or generalwell-being.

In one embodiment, said stimulus is a sensory, electrical and/ormagnetic stimulus.

In another embodiment, both stimuli are separated for a time comprisedfrom about 1 second to 2 seconds.

In another embodiment, the first stimulus is applied from about 0.1 toabout 1 second after the detection of the negative peak.

In another embodiment, the method of the invention further comprises theapplication of same stimuli during memory training or learning processwhile said subject is awake.

In another embodiment, the method of the invention is controlled by saidsubject.

In another embodiment, the method of the invention is controlled by askilled pratician.

In another embodiment, said subject is a healthy subject which undergoesnormal aging or a training period.

In another embodiment, said subject is affected by a memory-relateddisorder or a cognitive-related disorder.

In another embodiment, said subject is affected by a neuronalconnectivity disorder.

Another object of the present invention relates to a device forimplementing the method of the invention comprising:

-   -   a. a headband to monitor brain activity comprising at least two        electrodes, wherein one electrode is an active electrode to        detect SOs and the other is the reference electrode placed on        the mastoid part of the temporal lobe,    -   b. a stimulation device providing at least one type of stimulus,    -   c. a programmable microcontroller board.

Another object of the present invention relates to a device forimplementing the method of the invention comprising:

-   -   a. a headband to monitor brain activity comprising at least two        electrodes, wherein one electrode is an active electrode to        detect the end of stage I of a non-REM light sleep state and the        other is the reference electrode placed on the mastoid part of        the temporal lobe,    -   b. a stimulation device providing a first stimulus at the onset        of stage II of a non-REM light sleep state and a second stimulus        separated for a time from about 1 to about 2 seconds,    -   c. a programmable microcontroller board repeating step b. until        the end of stage IV, and.    -   d. said programmable microcontroller board restarting at step a.        when an onset of a further stage II is detected.

Definitions

In the present invention, the following terms have the followingmeanings:

-   -   “Affected” refers to the affliction of a subject having and/or        developing and/or at risk to develop a sleep-related disorder,        memory or a cognitive-related disorder.    -   “Sleeping state” refers to a progression of brainwave patterns        that may be monitored while a subject is sleeping. Generally,        subjects undergo several sleep cycles per night, each lasting        around ninety minutes. Each progression of brainwave patterns        during the sleep cycle may be referred to as a stage of the        sleep cycle.    -   “Sleep cycle” refers to consecutive stages that comprise: a        falling asleep state, a non-REM sleep state (light state and        then deep state) and briefly back to stage II sleep then REM        sleep state (during this stage the brain activity is intense,        quite close to that of awakening, there are very rapid eye        movements).    -   “Non-REM sleep state” refers to stage I (stage of transition        between wakefulness and sleep), stage II (stage of sleep        confirmed), stage III, stage IV sleep (stages III and IV are        characterized on the EEG by slow and loose waves, hence the name        of slow wave sleep).    -   “Non-invasive” means that no tissue is taken from the body of a        subject.    -   “About” preceding a figure and/or a score means plus or less 10%        of the value of said figure and/or score.

DETAILED DESCRIPTION

This invention relates to a non-invasive method for improving and/orconsolidating memory in a subject in need thereof and comprising:

-   -   a. monitoring a subject's sleeping cycle,    -   b. detecting the end of stage I of a non-REM light sleep state,    -   c. applying a first stimulus on said subject at the onset of        stage II of a non-REM light sleep state,    -   d. applying a second stimulus on said subject,    -   e. repeating applying the first stimulus and the second stimulus        until the end of stage IV, and    -   f. restarting said method at step c when an onset of a further        stage II is detected,

thereby extending slow wave sleep stages and modulating the sleeparchitecture of said subject.

Technics to monitor sleeping cycle in a subject include but are notlimited to: electroencephalography (EEG); electrooculography (EOG);electromyography (EMG); motion during sleep (called actigraphy measuredby image capture, accelerometer, microphone, or other techniques); heartrate, via accelerometer, pulse oximetry, ECG; respiratory rate, viaaccelerometer, microphone; and body temperature, via temperature probeor distant infrared (IR) sensor.

EEG records the neural activity of electrical potential across cellmembranes, which are detected through the cerebral cortex and recordedby a plurality of electrodes. The changes in electrical potential in thecortex contain rhythmical activity, which typically occur at frequenciesof about 0.5 to 70 cycles per second (hertz). While awake, fast, randomsignals are predominantly generated at low amplitude voltage and mixedfrequency. While asleep, more predictable signals are generated at ahigh amplitude voltage and predictable frequencies over predictableperiods.

Electrooculography (EOG) records the ocular activity of the electricalpotential from the retina, which consists of an electrically-chargednerve membrane. EOG signals can be measured by placing electrodes nearan eye. Motion of an eye may cause a measurable change of electricalpotential between two or more surface electrodes.

Electromyography (EMG) records the muscular activity of electricalpotential across muscular membranes, which range between about 50microvolts to about 300 millivolts (depending on the muscle underobservation). Typical repetition rate of muscle unit firing is about 7hertz to about 200 hertz, depending on the size of the muscle, the typeof muscle, etc. EMG signals may be recorded within a muscle (i.e.,intramuscular EMG) or on the surface a subject's skin outside of amuscle.

In one embodiment, one or more of those technics may be usedsimultaneously to monitor sleep cycle.

For example, a subject's EOG and/or EMG may also be useful indetermining the sleep cycle of a subject. For example, when phasic burstof EOG eye movements are seen during low EMG activity along withsimultaneous low voltage, mixed frequency EEG activity, the subject islikely to be in REM sleep.

Five distinct brain wave patterns that are commonly detected during anEEG recording are delta waves (e.g., about 0.5-3 hertz), theta waves(e.g., about 3-8 hertz), alpha waves (e.g., about 8-12 hertz), betawaves (e.g., about 13-38 hertz), and gamma waves (e.g., about 38-70hertz). Many of these frequencies may be observed in a subject's sleepcycle. A sleep cycle may be defined as a progression of brainwavepatterns that may be seen while a subject is sleeping. Generally,subjects undergo several sleep cycles per night, each lasting aroundninety minutes. Each progression of brainwave patterns during the sleepcycle may be referred to as a stage of the sleep cycle. Generally, eachsleep cycle progresses consecutively through stage I sleep, stage IIsleep, stage III sleep, stage IV sleep (stage III sleep and stage IVsleep may be grouped together and referred to as slow wave sleep),briefly back to stage II sleep, and then REM sleep.

In one embodiment, the stimulus of the invention provided may comprisean electrical or sensory stimulus. One or more forms of sensorystimulation includes, but is not limited to auditory, olfactory,tactile, somatosensory, gustatory, visual, vestibular or other sensorysystems stimuli. One or more forms of electrical stimulation include,but is not limited to: transcranial electrical stimulation. Other formsof stimuli include but are limited to: ultrasound, optical, magnetic,transcranial magnetic stimulation or another form of energy.Accordingly, the skilled artisan knows the best way of applying each ofthese stimuli.

In another embodiment, the stimulus of the invention comprises bonestimulation. In particular, the bone stimulation includes the vibrationof the bones of the inner ear.

In another embodiment, the stimulus of the invention is osteophonicstimulation.

In one embodiment, the choice of the stimuli is adapted to each subjectdepending on its sensitivity and/or ability to receive said stimuli.

In another embodiment, the intensity of the stimuli is adapted to eachsubject depending on its sensitivity and/or ability to receive saidstimuli.

In a further aspect of the invention, the stimulus described here aboveis applied while the subject is awake and is undergoing a trainingperiod or a learning process.

In another embodiment, a sensory stimulator is configured to provide anambient sensory stimulus recorded during the training session. Forexample, the sensory stimulator may comprise an ambient recorder forrecording the ambient stimulus wherein the ambient recorder isconfigured to record one or more of ambient sounds, ambient odors, andambient sensations.

In another embodiment, the stimulus may be optimized. In somevariations, the sensory stimulus provided may be optimized based on theinformation to be learned. For example, the stimulus provided may benon-interruptive, and may be configured to be innocuous so as not tointerrupt the concentration of the user during the training sessionand/or not to awaken or disrupt the user's sleep during sleepconsolidation.

In another embodiment, the stimulus is provided by third parties (e.g.advertisers) who pay to have a user train with a particular scent,jingle, or other stimulus during training with the device. In anotherembodiment, a user could purchase a single stimulus or set of stimulisimilar to how one buys a ringtone or rights to a copyright-controlledstock image.

In one embodiment, the stimulus is unique to a particular learningsession or subject matter. Thus, in variations the linking of thesensory stimulus to the subject matter may allow association acrosstraining sessions. For example, in some variations the system (e.g.,using control or system logic) may select stimuli for the purpose ofinvoking transitive inference between content to be learned. In a simpleexample, a user desires to associate the word “orange” with the pictureof an orange. While being presented with an olfactory cue, the user isalso presented the word “orange.” In another learning event, the sameolfactory cue is co-presented with the picture of an orange. The usersubsequently uses transitive inference to associate the word with thepicture, without having a simultaneous presentation of the two items.

In another embodiment, the stimulator is a non-distracting stimulus.

In another embodiment, the stimulator cannot awake the subject of theinvention.

In one embodiment, the subject may configure the stimulation to deliverdifferent types of stimulation to, e.g., correspond to different typesof awake learning tasks.

For example, a subject may configure an auditory stimulation device todeliver a first type of auditory or olfactory stimulation, such as,e.g., classical music (or classical music of a specific composer), whilethe subject is learning a selected type of material (e.g., math,grammar, history, etc.). In another example, a subject may configure theauditory stimulation device to deliver a second type of auditorystimulation, such as, e.g., ambient “water flowing” sounds, while thesubject is learning vocabulary. Still further, for example, a subjectmay configure the auditory stimulation device to deliver a third type ofauditory stimulation, such as, e.g., short auditory tones (e.g., about 1kilohertz or more, 2 kilohertz or less, etc. for about one-half secondor less, about 1 second or more, about 1 second or less, etc.), that areselected to correspond to a selected learning activity.

In another embodiment, the stimulation is applied after detection of theend of stage I of a non-REM-sleep state.

In another embodiment, the stimulation is applied after detection of theonset of stage II of a non-REM-sleep state.

In one embodiment, the stimulation is applied after detection of aspecific phase of ongoing SO. In one embodiment, the stimulation isapplied at the detection of negative peaks of SO.

In one embodiment, the first stimulation is applied at the detection ofnegative peaks of SO and the second stimulation is applied at thedetection of positive peak of SO.

SOs rhythms are different from a subject to another. Therefore, themethod of the invention can adapt the stimulation to each subject.

In one embodiment, the stimulation applied in the method of theinvention enhances other rhythms than slow waves.

In one embodiment, the stimulation is applied at the detection of sleepspindles. Sleep spindles are bursts of brain waves that may benetworking between key regions of the brain to clear a path to learning.These electrical impulses help to shift fact-based memories from thebrain's hippocampus, which has limited storage space, to the prefrontalcortex's “hard drive”, thus freeing up the hippocampus to take in freshdata. Spindles are fast pulses of electricity generated during non-REMsleep, and they can occur up to 1,000 times a night. This spindle-drivennetworking is most likely to happen during stage II of non-REM sleep,which occurs before we reach the deepest non-REM sleep and the dreamstate known as REM sleep.

In another embodiment, the stimulation is applied when a peak is havingamplitude inferior to −75 μV. In another embodiment, the stimulation isapplied when a peak is having an amplitude from about 50 to about 150μV.

Methods to detect negative peaks are well known in the state of the artand are described hereabove.

In one embodiment, the non-invasive method of the invention comprisesthe application of stimuli that are separated for a time comprised fromabout 1 second to about 2 seconds. In another embodiment, the timecomprised between stimuli applications is adapted to each subject.

In one embodiment, the non-invasive method of the invention comprisesthe application of first stimuli that are separated for a time comprisedfrom about 0.1 to about 1 second, preferably 0.4 to 0.6 seconds afterthe detection of the negative peak. Most preferably, the non-invasivemethod of the invention comprises the application of first stimuli thatare separated for a time of about 0.5 seconds after the detection of thenegative peak. After the first intervention (stimuli), a second stimulusis triggered with a delay of about 0.8; 0.9; 1; 1.1; 1.2; 1.3; 1.4; 1.5;1.6; 1.7; 1.8; 1.9 seconds. Preferably, the non-invasive method of theinvention comprises the application of a second stimulus separated for atime of about 1.25 seconds from the first stimulus. In anotherembodiment, the non-invasive method of the intervention comprises theapplication of train of several stimuli that are separated for a time ofabout 1.25 seconds after the first intervention.

The person skilled in the art knows that sleep cycle is different from asubject to another depending on diverse factors that include but are notlimited to: age, sex, environmental conditions, a disease that mightaffect said subject etc. . . . .

In one embodiment, said intensity of said first and second stimuli isequal.

In another embodiment, said intensity of said first stimulus is lowerthan the intensity of the second stimulus.

In another embodiment, said intensity of said first stimulus is higherthan the intensity of the second stimulus.

In one embodiment, the length of an auditory stimulation is from about25 to about 100 ms, preferably 50 ms.

In another embodiment, the length of an auditory stimulation is 50 ms.

In another embodiment, the length of an auditory stimulation is adaptedto each subject.

In one embodiment, the amplitude of an auditory stimulus is from 40 to70 dB.

In another embodiment, the amplitude of an auditory stimulus is about 65dB.

In another embodiment, the amplitude of an auditory stimulation isadapted to each subject.

In one embodiment, the intensity of transcranial electrical stimulationsis from about 0.3 to about 0.2 mA.

In another embodiment, the frequency of transcranial electricalstimulations is from about 0.5 to about 1 Hz, preferably about 0.8 Hz.

In one embodiment, said non-invasive method is performed at thehospital.

In another embodiment, said non-invasive method is performed at home.

In one embodiment, said non-invasive method is controlled by thesubject.

In another embodiment, said non-invasive method is controlled by theskilled pratician.

In one embodiment, the subject of the invention is a mammal, preferablya human. In one embodiment, the subject is female. In another embodimentthe subject is a male.

In one embodiment, the subject of the invention is an adult. In oneembodiment, the term “adult” may refer to subjects of more than 20 yearsold to about 65 years old.

In another embodiment, the subject of the invention is a young subject.In one embodiment, the term “young subject” may refer to subjects fromabout 8 to about 20 years old.

In another embodiment, the subject of the invention is a senior person.The term “senior person” may refer to subjects from about 65 years old.

In another embodiment, the subject is a healthy subject which undergoesnormal aging.

In another embodiment, the subject is a healthy subject which undergoesa training period.

In another embodiment, the subject of the invention is affected by asleep-related disorder.

In another embodiment, the subject of the invention is not affected by asleep-related disorder.

In another embodiment, the subject of the invention is affected byepilepsy.

In one embodiment, the subject of the invention is not affected by adepressive disorder.

In another embodiment, the subject of the invention is affected by amemory-related disorder or a cognitive-related disorder. Examples ofmemory or cognitive-related disorders include but are not limited to:Alzheimer's disease, Down syndrome, Parkinson's disease, frontotemporaldementia, epilepsy, stroke, Rett syndrome, Huntington's disease, autismspectrum disorder, Fragile X syndrome, neurofibromatosis type 1,tuberous sclerosis, phenylketonuria, maple syrup urine disease,chemotherapy treatment, radiation therapy, post-traumatic stressdisorder, drug or alcohol use.

In another embodiment, the subject of the invention is affected by aneuronal connectivity disorder in the absence of obvious anatomical,proliferative or degenerative anomaly. Examples of such disordersinclude in a non-limited list: schizophrenia and other psychiatricdisorders, and autism.

This invention also relates to a non-invasive method for enhancingand/or consolidating memory comprising:

-   -   a. monitoring sleeping cycle,    -   b. detecting the end of stage I of a non-REM light sleep state,    -   c. emitting a first stimulus at the onset of stage II of a        non-REM light sleep state,    -   d. emitting a second stimulus,    -   e. repeating applying the first stimulus and the second stimulus        until the end of stage IV, and    -   f. restarting said method at step c. when an onset of a further        stage II is detected, thereby extending slow wave sleep stages        and modulating the sleep architecture.

The present application also relates to a non-invasive method formodulating sleep architecture comprising:

-   -   a. monitoring sleeping cycle,    -   b. detecting the end of stage I of a non-REM light sleep state,    -   c. emitting a first stimulus at the onset of stage II of a        non-REM light sleep state,    -   d. emitting a second stimulus,    -   e. repeating applying the first stimulus and the second stimulus        until the end of stage IV, and    -   f. restarting said method at step c. when an onset of a further        stage II is detected,

thereby improving memory consolidation and/or cognition and/or generalwell-being.

The term “modulating sleep architecture” as used herein refers to anextension or a reduction of slow wave sleep stages. The technics todetermine a modulation of sleep architecture are well known to theskilled artisan and are described here above.

In one embodiment, the method of the invention aims at improving thesleep quality and efficiency in a subject, as measured and scoredquantitatively during sleep, upon awakening, and during waking hours,for short, medium, and long periods of time.

The present application also relates to a device for implementing themethods of the present application to a subject in need thereof.

In one embodiment, the device of the present application comprises:

-   -   a. a headband to monitor brain activity comprising at least two        electrodes, wherein one electrode is an active electrode to        detect SOs and the other is the reference electrode placed on        the mastoid part of the temporal lobe,    -   b. a stimulation device providing at least one type of stimulus,    -   c. a programmable microcontroller board.

The present application also relates to a device comprising:

-   -   a. a headband to monitor brain activity comprising at least two        electrodes, wherein one electrode is an active electrode to        detect the end of stage I of a non-REM light sleep state and the        other is the reference electrode placed on the mastoid part of        the temporal lobe,    -   b. a stimulation device providing a first stimulus at the onset        of stage II of a non-REM light sleep state and a second stimulus        separated for a time from about 1 to about 2 seconds,    -   c. a programmable microcontroller board repeating step b. until        the end of stage IV, and.    -   d. said programmable microcontroller board restarting at step a.        when an onset of a further stage II is detected.

The present application also relates to a device comprising:

-   -   a. a headband to monitor brain activity comprising at least two        electrodes, wherein one electrode is an active electrode to        detect the end of stage I of a non-REM light sleep state and the        other is the reference electrode placed on the mastoid part of        the temporal lobe,    -   b. a stimulation device providing a first stimulus at the onset        of stage II of a non-REM light sleep state from about 0.1 to        about 1 second after the detection of the negative peak and a        second stimulus separated for a time from about 1 to about 2        seconds,    -   c. a programmable microcontroller board repeating step b. until        the end of stage IV, and.    -   d. said programmable microcontroller board restarting at step a.        when an onset of a further stage II is detected.

In one embodiment, the device may include a power supply, a controlsystem, a display system, at least one electrode, and/or any othercomponent as would be known by the skilled artisan. The monitoringdevice may be autonomous, or may be operated by an operator.

Electrodes of the invention include but are not limited to: dryelectrodes, cloth electrode, gel electrode, disposable electrode,reusable electrodes, integrated gel electrode, needle electrode.

In one embodiment, the subject may self-administer the device. In oneembodiment, the device may be stationary or portable (in which case itmay include a portable power supply).

The present application also relates to a monitoring device which candetermine the brain activity of said subject. The electrodes of thedevice may be positioned proximate the subject's head to monitor, e.g.,one or more selected portions of the subject's brain and/or head, etc.For example, the electrodes may be positioned proximate the subject'seyes, forehead, frontal lobes, temporal lobes, parietal lobes, occipitallobes, the cerebral cortex overlaying the hippocampus, amygdala, etc. Inone embodiment, the reference electrode is positioned in the mastoidpart of the temporal bone behind the ear. The one or more selectedportions of the subject's brain and/or head to be monitored by thedevice may be selected based on what portions of the brain may beinvolved in the task at hand. Additionally, the monitoring device maymonitor the state of consciousness or sleep stage the subject is in atany given moment. For example, a subject's frontal lobe just above theeye may be monitored by the device because the stage of sleep may bedetermined through an analysis of brain waves (e.g., EEG), eye movements(e.g., EOG), and muscle tone (e.g., EMG).

In one embodiment, the device of the invention includes a headband tomonitor brain activity of said subject. In particular, the headband maycomprise electrodes to monitor EEG signals, EOG, EMG, electrodereference. A headband and signal processing unit may be charged byplacing the unit on a docking station mounted on the top of theenclosure. The docking station may be connected to an EEG PCB board thatincludes various signal processing and wireless communicationfunctionalities. Placing the headband unit in the docking stationmatches the headband unit to the EEG PCB board for subsequent wirelesscommunication. The EEG PCB board in this example also includes a serialcommunication port that transmits a serial stream of data correspondingto the user's sleep state, time stamps, and other information. Theserial stream is received and parsed by the programmablemicrocontroller.

In one embodiment, the device of the invention further comprisesfilters, in particular filters adapted to SO patterns. The EEG signal isfiltered out so that the raw EEG data can be graphically displayed andthe EOG signals can be filtered. The EOG signals may be filtered usingthe known JADE algorithm to filter noise. Then, the EEG and EOG signalsare low pass filtered and then the signals are Hanning windowed. Thefiltered EEG data signals are generated and can be graphed. Then, thefiltered signals are analyzed for their power spectrum, which are thenfed into the neuro-algorithms so that the mental and emotional states ofthe user are determined. Using the power spectrum analysis, the powerspectrum data for the delta, theta, alpha and beta waves are extracted.Examples of filters include but are not limited to Chebyshev Type IIfilters, Butterworth filters and elliptic filters.

In one embodiment, the device of the invention further comprisesfiltering an EEG signal of a user, comparing two filtered bands of theEEG signal through spectral analysis, and extracting stablephase-difference (e.g., decoupling) or phase-locking (e.g., coupling)episodes between the two signal bands via statistical identification ofphase-locking synchrony.

In this embodiment, a programmable microcontroller board applies controllogic that determines device function based on user inputs, the user'ssleep state or state of wakefulness, and previous device use by theuser. For example, an Arduino open source microcontroller framework isan effective programmable microcontroller board used in this embodiment.The Arduino system includes digital inputs and outputs, analog inputsand outputs, serial receiver, serial transmission, and power (both 5Vand 3.3V). The microcontroller system in this example is programmed withcustom software for controlling the various elements of the system formemory enhancement.

In one embodiment, the microcontroller begins by first checking whetherthe device is in Training Mode or Sleep Mode. If the device is in SleepMode, the microcontroller begins reading information via a serialcommunications receiver in real-time from sleep-phase detectioncircuitry. When the user puts on the EEG headband unit, an LED indicator(the headband LED indicator, LED1) is turned on by changing theappropriate digital output of the microcontroller to a high (5V) state.The microcontroller parses sleep stage information for the user andstores these data with timestamps in a memory component of the device.If the incoming sleep data indicates the user is in a slow-wave sleepepoch, scent delivery logic is activated by changing the appropriatedigital output to a high (5V) state. The activation of the scentdelivery logic is also registered on the memory component of the devicewith a timestamp. While slow-wave sleep is occurring, the time ofoperation is identified and compared to a training schedule, such thaton appropriate days, scents are delivered. The device loads, reads, andparses a user configuration file stored on the device memory todetermine the appropriate device function based on the training schedulefor the user. The selection of which scent to deliver and the quantityof scent delivered is also determined by the training schedule. An LEDindicator, stimulus indicator (the scent LED indicator, LED2), is turnedon when the scent is delivered during sleep by changing the appropriatedigital output of the microcontroller to a high (5V) state. The LEDindicator can be left on for the remaining portion of the night so thatthe user can observe it upon wakening. In such embodiments, the controllogic turns off LED2 at a fixed time (e.g. 2 hours) after the userwakes. When the slow-wave sleep epoch ends as determined by theregistration of a different sleep state by the sleep state monitoringcomponents of the system, the scent delivery logic is changed toinactive and scent release ceases. While the subject is in non-slow wavesleep states, scent delivery logic is not active. If the device is notbeing used during sleep, the microcontroller does not acquire sleepinformation from the associated EEG hardware and no scents are released.

If the device is in Training Mode, the microcontroller digital outputsare changed to high (5V) for LED2 and the appropriate scent deliveryunit as determined by the training schedule for the user. At the end ofa Training Mode session, the user toggles the position of the userinterface switch and the microcontroller responds by changing theappropriate digital outputs to turn off LED2 and cease scent delivery.

In one embodiment, the device described herein may combine multiplemodules into a cohesive system. These modules or components may includecontrol logic (e.g., software, firmware, hardware, or the like) whichmatches learning content with associated sensory stimuli delivered, andhardware (e.g., sensory stimulators) such as scent dispensers or audiospeakers and/or recorders. During sleep, monitoring hardware such aselectroencephalography (EEG) for recording brain rhythms may be analyzedby logic (e.g., algorithms or logic for detecting deep sleep, such asslow-wave, or delta, 0.5-4 Hz, rhythms in the EEG signal) or other sleepstages and then triggering presentation of sensory stimuli (e.g., soundsor smells).

In another embodiment, the device may include sleep monitoring that canidentify particular stages of sleep and communicate this information toa device that determines whether to deliver sensory stimuli and, if so,which sensory stimuli to deliver at which sleep stage to a particularuser. In one embodiment, sleep monitoring may be accomplished byelectroencephalography (EEG) and the sleep state during which sensorystimuli are delivered may be deep sleep identified on the basis of oneor more brain rhythms such as delta rhythms (generally about 0.5-4 Hz)and/or the absence of muscle activity related to eye or other movementsgenerally indicative of other stages of sleep.

In another embodiment, the quantity or quality (e.g. intensity) of aparticular stage of sleep that may be deep sleep can be increased ordecreased by delivering sensory stimuli or electrical stimulation.

In another embodiment, the choice of sensory stimulus and/or itsintensity and/or its rate of repetition can be adjusted based on thelevel of arousal of the user during sleep.

In another embodiment, performance may be monitored by the system totest memory performance the following day. The platform may use wirelessand internet-based networking technologies to access a database that mayinclude learning content, sensory stimuli, and/or sleep monitoringparameters in order to optimize system performance for an individualuser or patient population.

In a further embodiment, the device comprises a stimulation device.Stimulation device may include, e.g., a power supply, a control system,a display system, headphones, speakers, tapes, compact discs, memory,tactile pad or tablet, scent release system and/or any other componentas would be known by the skilled artisan. The monitoring stimulationdevice may work in conjunction with a portable audio device like, e.g.,an Apple iPod, a MP3 player, a compact disc (CD) player, etc. Further,the stimulation device may be a non-portable audio device like, e.g., ahome stereo system, radio, etc.

In another embodiment, the device may include one or a plurality of userinterface components that allow a user to control whether the device isin training mode. The user interface is generally configured so that thedevice may be controlled by the user without requiring additionalassistance. The user interface may also allow the user to select otherparameters of device function. The device may also include one or aplurality of stimulus generators (optionally referred to as stimulusactuators) capable of activating at least one sensory transductionpathway. The device may also include one or a plurality of sensors thatmeasure user physiology to determine the sleep state of the user. Thedevice may include logic that estimates the sleep state of a user fromrecorded physiological and other data. The device may also include acontroller comprising control logic that determines the device functionbased on user inputs, the user's sleep state or wakefulness, andprevious device use cases by the user.

In another embodiment, the device also includes one more outputs (useroutputs) such as screens, light emitting diodes (LEDs), or othercomponents to indicate device function. The device may also include oneor more switches or other control elements for the user to controldevice function. In some variations the device includes acomputer-readable/writeable memory component (local or remote). Inanother embodiment, the device includes a controller and control logic;the device may also include send/receive sub-systems for transmission ofdata between the device and an off-site computer.

In one embodiment, the device includes a secured system for transmissionof data to the skilled patrician, or a medical care unit able to analyzesuch data. In one embodiment, such data may be used for a researchprogram or used for a reference value in cohort study. In anotherembodiment, such data may be used for medical care.

In another embodiment, a wireless communication system (Bluetooth) maybe provided to transmit the raw and/or processed signals to an EEGreceiver board component of the device. In particular, EEG signals areanalyzed by the skilled patrician to adapt the method of the inventionto the subject in need thereof.

In one embodiment, the device may be controlled externally. Forinstance, the stimuli train is adapted to each subject by the skilledpatrician by a controlled feedback system on the device of theinvention.

In one embodiment, the device of the invention may use trainingoptimization algorithms to determine what content is presented at whatinterval to reduce the amount of time required for training.

In another embodiment, the device described herein may also includelogic for efficient memory training and memory consolidation duringsleep. In some embodiments, an additional aspect of feedback is used tooptimize (or improve) the frequency of repetition by recording on thedevice itself or through the Internet on a remote server, or through anintermediate device. Established techniques for optimizing therepetition time in a spaced repetition implementation may be based ondetailed mathematical models of learning and may take into account theopportunity cost of forgetting and content repetition. These algorithmscan be used to improve the performance of the present invention for aparticular user, subset of users, or class of users defined by age,gender, cognitive ability, interests, or any clinically relevant causeof cognitive dysfunction.

In one embodiment, optimization can be applied to various components ofthe present application, including the rate of repetition of trainingstimuli, the amount of learned material or specific set of contentassociated with a particular stimulus or class of stimuli, the salienceof stimuli associated with training stimuli, or other aspects.

In another embodiment, the device may use analytical and/or data miningtechniques to determine interests, experiences, and/or previouslylearned content in order to select a stimulus or set of stimuli thatengage transitive inference processes between previous experience andnew learning content. These techniques may be provided as logic (e.g.,stimulus selection logic) configured as hardware, software, firmware, orthe like.

In another embodiment, an automated algorithm (relationship logic)determines which content that has been added to a user's contentdatabase is related, similar or coupled (e.g. all the state capitals,the word ‘sleeping’ in different languages, or a sequence of stepsrequired to perform CPR), then applies the same sensory stimulus (e.g.the sound of snoring or the scent of a rose) for these pieces oftraining content, even if the learning events are separated in time byminutes, hours, days, weeks, months, or years. This embodiment may beconsidered as related to the concept of transitive inference. In arelated embodiment, a curated service, third party, or socially-derivednetwork may determine whether content to be learned is related, similaror coupled and may use this determination to determine whether the sameor similar sensory stimulus should be presented for these items ofcontent to be learned. In another embodiment, the determination ofwhether training content is related for purposes of choosing identicalor similar stimuli to present during training may be made based onwhether other users have coupled such content. For instance, if otherusers had experienced memory improvements due to transitive inference byusing a similar stimulus to associate with content to be learned.

In one embodiment, the device of the invention monitors the user toautomatically determine the sleep phase for the subject, and triggerreplay of the sensory stimulus upon or after detection of a particularsleep phase. The sleep phase may be a typical sleep stage (e.g.,slow-wave sleep) or a variation of a typical sleep stage.

In one embodiment, the device described herein may be configured so thatthe specified sleep stage is predetermined from the known sleep stages(e.g., slow wave sleep, light sleep, REM sleep, phases S1, S2, S3, or S4of non-REM sleep, etc.) or combinations of sleep stages. For example, insome variations the sleep stage is slow wave sleep. In some variations(e.g., for reconsolidation of amygdala memories that may be importantfor PTSD) the sleep stage is rapid eye movement sleep.

In another embodiment, the device described herein may comprise the useof one or more techniques (e.g., electrical stimulation, sensorystimulation or other methods) to induce brain rhythms at deltafrequencies to modulate the functional properties of slow-wave sleep toimprove memory consolidation processes. Similarly, the device of theinvention may use electrical stimulation, sensory stimulation or othermethods to disrupt brain rhythms at delta frequencies to modulate thefunctional properties of slow-wave sleep to interfere with memoryconsolidation processes. Electrical stimulation, sensory stimulation orother techniques may be used to induce brain rhythms at otherfrequencies or with other spatial temporal patterns in order to affectbrain rhythms and underlying cognitive processes.

In another embodiment, the device of the invention described herein usefeedback from recording or monitoring of physiological or otherparameters that correspond to sleep state or arousal level to define theintensity, modality, and/or specific stimulus delivered during sleep.

In another embodiment, described herein are methods for improvingmemory. These methods may have a training mode and a sleep consolidationmode, and may include: a user interface comprising a control allowing auser to switch the device to the training mode to indicate a trainingsession; a sensory stimulator configured to provide a plurality ofdistinct sensory stimuli; a sleep monitor configured to monitor a user'ssleep state; and a controller comprising control logic receiving inputfrom the user interface and configured to select a distinct sensorystimulus for a specific training session and to control the applicationof the distinct stimulus during the specific training session, andfurther wherein the controller receives information on the user's sleepstate from the sleep monitor, and controls the sensory stimulator toapply the distinct sensory stimulus from the specific training sessionwhen the user is experiencing a specified sleep stage during a sleepconsolidation mode following the specific training session.

In some embodiments, the device described herein may include a memory(e.g., a computer or digitally readable/writable memory). This memorymay be connected directly or remotely to the controller. The memory maybe configured to store information that indicates one or more of: whichsensory stimuli have been applied for specific training sessions, thesleep state of user, and completion of application of a sensory stimulusduring a sleep consolidation mode following a specific training session.In some variation the memory is important for storing and providing userconfiguration. For example, the device may read a user configurationfile or memory to determine what sensory stimuli have been used, or areavailable for use, and/or for determining what training has occurred, orhas been paired with a sensory stimuli. The configuration file may alsostore user information (e.g., biometric information) and/or accessinformation. The controller may be configured to read information fromthe memory.

In general, the user interface is adapted so that the user may readilyand easily control operation of the device. For example, the userinterface may include at least one of: a switch, a toggle, a button, aslider, a knob, or a touchscreen, and may indicate (via instructions,menus, or the like) what options the user may select. The user interfacemay provide visual, audible, or tactile feedback on the status oroperation of the device.

In some embodiments, any appropriate sleep monitor may be used. Thedevice may include sleep monitoring logic to determine (based typicallyon information provided by a sleep monitor) what sleep state the user isin. This determination may be probabilistic (e.g., the logic mayindicate a user is in a particular sleep state, or is not even sleeping,when user indicators (e.g., movement indicators, thermal indicators,electrical indicators, etc.) indicate that the likelihood of aparticular sleep state is above some threshold). In some variations thesleep monitor comprises a non-contact sleep monitor. For example, thesleep monitor may be positioned near the sleeping user and may indicate(based on motion) an approximation of which sleep state the user is in.

In some embodiments, the device described herein may include a handle.In general, the device of the invention is intended for a user tooperate without requiring additional assistance, at home (e.g., forpersonal use).

In some embodiments, the device described herein may include acommunication module coupled to the controller configured to allowcommunication with a remote site. For example, also described herein areportable user-controllable devices for improving memory, the devicecomprising: a user interface comprising a control allowing a user toplace the device into a training mode indicating a training session; asensory stimulator configured to present a plurality of distinct sensorystimuli; sleep monitoring logic configured to determine when the user isin a specified sleep state; and a controller comprising control logicconfigured to determine a specific sensory stimulus received by the userconcurrent with a particular training session; wherein the controller isfurther configured to reapply the specific sensory stimulus when theuser is in a specified sleep state following the training session. Asmentioned, the portable device may include a housing at least partiallyenclosing the user interface, sensory stimulator, and controller. Theportable device may also include a sleep monitor configured to monitorthe user's sleep state.

In one embodiment, the device described herein may be configured to useambient sensory stimuli, including ambient noise. In some variations thesystem or device may therefore include an ambient recorder for recordingthe ambient stimulus. The ambient recorder may be part of the sensorystimulator, or it may be a separate element. For example, an ambientrecorder may be configured to record one or more of ambient sounds,ambient odors, and ambient sensations.

In another embodiment, the sensory stimulator is configured to accessone or more sources of ambient stimuli that are active during thetraining session. The one or more sources of ambient stimuli may includeone or more of: audio players, computers, televisions, mobile devices,scent releasing devices, and massage/vibratory devices, or any otherdevice configured to deliver a sensory stimulus to the user.

In another embodiment, the device of the invention comprises methods forimproving memory with a user-controlled device. For example, the methodmay include the steps of: selecting, in a user-controlled device, aspecific sensory stimulus that is received by the user during a firstlearning period; detecting, with the user-controlled device, a specifiedsleep stage in the user following the first learning period; anddelivering, from the user-controlled device, the specific sensorystimulus to the user during the specified sleep stage following thefirst learning period.

In another embodiment, the method of the invention further includesdelivering, from the user-controlled device, the specific sensorystimulus to the user during the first learning period. In somevariations the method includes using ambient sensory stimuli. Forexample, the method may include selecting the specific sensory stimulusby recording an ambient sensory stimulus during the first learningperiod.

In one embodiment, the method and device of the invention are useful forachieving effective modulation of memory consolidation during sleep.

In another embodiment, the method and device of the invention achieveeffective modulation of cognition or memory over one or more days and/ornights, including devices and methods for configuring, populating, andquerying a learning database with training content and contextualsensory stimuli co-presented with the training content, as well asdevices for selecting, prioritizing, and scheduling contextual sensorystimuli to be presented during study and sleep. The device of theinvention is configured to determine how to use training content fromthe learning database to determine a training schedule for repetition ofsensory stimuli associated with particular training content over one ormultiple nights of sleep.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 represents diagrams showing stimulation procedures in humanbrain.

FIG. 2 is a histogram showing the effect of stimulation on the amplitudeof sleep slow oscillations.

FIG. 3 is a graph showing the effect of stimulation on the number ofslow waves sleep.

FIG. 4 represents recordings of the sleep architecture before and afterstimulation of the human subject.

FIG. 5 represents diagrams showing recordings and stimulation proceduresin the animal model.

FIG. 6 represents diagrams showing sensory stimulations applied duringthe down state increase the number of up and down states and SO.

FIG. 7 represents diagrams showing sensory stimulations in phase withthe ongoing up and down state oscillations modulate the pattern ofaction potential discharge in sensory cortical neurons.

FIG. 8 represents recordings of SO shapes alongside with a stimulationphase histogram of a fixed double stimulation protocol (A) and anadaptative double stimulation protocol (B).

FIG. 9 represents diagrams showing recordings, SO detection andstimulation procedures in the animal model. (A). Simultaneouselectrocorticographic (ECoG) and intracellular (Vm) recordings fromsomatosensory pyramidal neurons illustrating the probability of evokingan SO as a function of the stimulation phase (B).

EXAMPLES

The present invention is further illustrated by the following examples.

Example 1 In Vivo Experiments in Human Brain

In human subjects, brain activity is monitored online from a singlechannel (international 10-20 system, FPZ or Fp1 o1r Fp2) referenced tothe average potential from electrodes attached to the mastoids (M1 andM2) (FIG. 1-A). During sleep, the stimuli are presented for the firsttime at the onset of stage 2 (associated with sleep spindles at 11 to 15Hz) (FIG. 1-B). Furthermore, the stimulations are given at a specificphase of ongoing SO. For this purpose, the EEG is recorded and filteredonline below 3 Hz using an equiripple Finite Impulse Response (FIR)filters. Each time the filtered EEG signal crossed an adaptive thresholdset at large negative values (default −75 μV), two auditory stimulationsare triggered (FIG. 1-C). A command sends the sensory stimulation 500 msafter the detection. Then, a second stimulation is provided 1.25 secafter first stimuli. For auditory stimulations, the tones are bursts ofpink 1/f noise of 50 ms duration. Sound volume was calibrated to 65 dBSPL. Using this closed-loop feedback system, this system is able toenhance and extend trains of SOs during sleep (FIGS. 2-3). In contrastto previous reports (Ngo H V, et al. 2013 Neuron 78, 545-553), theincreased occurrence of SO trains after stimulation translates into anoverall increased number of identified SO in SWS. Furthermore, thesystem induces significant differences in sleep architecture during thestimulation period and extends SWS stages (FIG. 4).

Example 2 In Vivo Experiments in Animals

Acute experiments in animals are conducted in parallel with humanstudies. These pre-clinical investigations, by allowing multi-scale(from neuronal population to single neurons) electrophysiologicalrecords, offer the possibility to determine the cellular and networkmechanisms underlying sensory-evoked SO in humans. Simultaneous in vivoelectrocorticographic (ECoG) and intracellular recordings of barrelcortex pyramidal neurons are performed in the anaesthetized rat (MahonS, et al. (2012) J Neurosci. 32:11377-89; FIG. 1A, left). The barrelcortex is a specific region of the primary sensory cortex which receivesand integrates sensory information from the whiskers. Rodents use thesehighly specialized sensory organs on their snout to constantly acquiresensory information from their environment (Petersen C C et al. Neuron.2007 Oct. 25; 56(2):339-55). Rats are sedated by a systemic injection ofa mixture of ketamine and xylazine, a pharmacological proceduregenerating a brain activity, including ECoG and intracellular patterns,highly similar to that encountered during SWS in humans and rodents(Destexhe A, et al. 2007 Trends Neurosci. 30: 334-42). In this model,ECoG activity is characterized by the recurrence of SO at ˜1 Hzreflecting the alternance, at single cortical cell level, of prolongeddepolarizations associated with action potential firing (up state, US)and periods of neuronal silence (down state, DS) (FIG. 5-A, right).Whisker stimuli (W Stim.) consisted in short puffs of air at lowpressure (50 ms, 4-20 psi) delivered to whiskers contralateral to thesite of neuronal recordings. Whisker stimuli were given at specificphases of the up and down states cycle using a close-loop feedbackstimulation system (FIG. 5-B). Intracellular activity of single sensorycortical neurons is monitored and an adaptive voltage threshold (VTh) isused to detect transitions between up and down states. When the membranepotential (Vm) fell below Vth, an up to down state transition (UtoD) isdetected. Conversely, when Vm rose above VTh, a down to up statetransition (DtoU) is detected (FIG. 5-B). A transistor-transistor logic(TTL) pulse commands the sensory stimulation system with a given delay(Δt) after the detection of the transitions. Varying the time delaysafter transitions detection permits to explore and determine the beststimulation parameters (delay and intensity) for an optimal enhancementof SO. In some experiments, instead of sensory stimuli, we applynegative and positive direct current pulses through the intracellularelectrode to test for changes in the excitability (i.e., the ability tofire an action potential) of cortical neurons during the up and downstate cycle (FIG. 5-B). This will allow us to correlate possible changesin cortical excitability with the effectiveness of sensory stimuli intriggering SO.

Sensory stimuli given more than 150 ms after a transition to the downstate are effective in inducing and increasing up down statesoscillations in barrel cortex neurons. This effect is also visible atthe level of the cortical neurons population expressed as sensory-evokedSO in the EcoG (FIG. 6). Sensory stimulation in phase with thespontaneous ongoing up and down state oscillations (i.e, sensory stimuliat 1 ms after the detection of a DtoU transition) are able to modify thepattern of action potential firing in the up state phase (FIG. 7). Thischange in firing pattern could be essential for the induction ofcortical plasticity (Chauvette S et al. J Neurosci. 2011 Oct. 19;31(42):14998-5008).

This is a crucial point since long-term synaptic plasticity isconsidered as a plausible cellular mechanism underlying sleep-dependentmemory formation (Chauvette S et al. 2012 Neuron. 75:1105-13). In futureexperiments, to determine if sensory stimulations can trigger long-termplasticity at cortical synapses, the amplitude of synaptic responsesevoked by local electrical stimulation, or by sensory stimuli, will becompared before and after the application of boosting stimuli. We willalso search for long-term modifications in the intrinsic excitability ofcortical neurons (Mahon S, et al. 2012 J Neurosci. 32:11377-89) thatcould also participate to memory formation (Daoudal G, et al. 2003 LearnMem. 10:456-65).

CONCLUSION

It is thus expected that our new system can work as an artificialenhancer to boost natural sleep brain waves, including SO but also othersleep oscillations like thalamo-cortical spindles and hippocampalripples. Because all these sleep oscillations are associated with memoryprocessing, it is anticipated that the system can be applied in clinicalsettings to restore normal memory performance. Indeed, a number ofdisorders and diseases are accompanied by changes in sleep patterns anddysfunctions of memory, such as depression (Daoudal G, et al. 2003 LearnMem. 10:456-65), post-traumatic stress disorder (Steiger A et al. 2013Pharmacopsychiatry 46 (Suppl.1), S30-S35), Alzheimer's disease (GermainA 2013 Am. J. Psychiatry 170, 372-382) and schizophrenia (Wang G et al.2011 Trends Neurosci. 34, 452-463). Also, SWS gradually reduces aspeople age, and may even be entirely absent after 65 or 70. The declineof memory is correlated with a reduction of SWS (Lu W and Goder R 2012Sleep Med. Rev. 16, 389-394). In normal aging, closed loop stimulationfor sleep enhancement can help the maintenance of healthy cognitivefunction and memory consolidation.

Example 3 Optimized Stimulation Protocols for Enhancing SOs

The time between the minimum SO deflection and its subsequent maximum ishighly variable. Therefore, following a fixed double stimulationprotocol (FIG. 8A), it can be observed that, while satisfactory resultsare obtained for the first stimulation (A, right: stimulation phasehistogram alongside the corresponding SO shape), the second stimulationis often not at the maximum of the SO. Therefore we developed an adapteddouble stimulation protocol in which the stimulation timing is fitted tothe SO period (K) and subsequent minimum points. The detection steps ofthe adaptative protocol (FIG. 8B) are:

-   -   1) Detection of the negative pic (lower than the threshold) of        the SO;    -   2) Estimation of period K of the current wave (by zero crossing)        and stimulation at adapted time K/2;    -   3) Detection of the second negative pic and stimulation.

This protocol gives a better precision for the second stimulation mostlytriggered during the maximum of the SO (FIG. 8B, right: stimulationphase histogram alongside the corresponding SO shape).

Simultaneous electrocorticographic (ECoG) and intracellular recordingsfrom somatosensory pyramidal neurons are performed in rats underketamine-xylazine (FIG. 9A-B). Slow oscillations (SO) in the ECoG arereflected by an alternation of depolarizing up-states (US) andhyperpolarizing down-states (DS) in cortical neurons. An adaptativevoltage threshold (VTh) is used to detect transitions between US and DS.A high-voltage pulse commands the sensory stimulation system (W stim.)with a given delay (Δt) after the detection of the transitions. Varyingthe time delays after transitions detection permits to explore anddetermine the best stimulation parameters for an optimal enhancement ofSO. Sensory stimuli delivered during the DS (75 or 150 ms after atransition to the DS) are more effective in triggering new oscillationsin cortical neurons and networks compared to sensory stimuli deliveredduring the US.

1.-15. (canceled)
 16. A non-invasive method for monitoring a subject'sbrain activity and emitting stimuli according to said subject's brainactivity, said method comprising: I. receiving a brain activity signalmeasured by a monitoring device for measuring said subject's brainactivity; II. monitoring said brain activity signal, III. detecting insaid brain activity signal an end of a stage I of a non-REM light sleepstate, by detection of a negative peak with an amplitude inferior to −75μV, and an onset of a stage II of said non-REM light sleep state, IV.emitting a first stimulus at the detection of the onset of stage II ofsaid non-REM light sleep state, V. emitting a second stimulus, VI.repeating emitting the first stimulus and the second stimulus until anend of a stage IV of said non-REM light sleep state, and VII. restartingsteps IV to VII when an onset of a further stage II of said non-REMlight sleep state is detected.
 17. The non-invasive method according toclaim 16, wherein said first or second stimulus is a sensory, electricaland/or magnetic stimulus.
 18. The non-invasive method according to claim16, wherein both stimuli are separated for a time comprised from about0.5 second to 2.5 seconds.
 19. The non-invasive method according toclaim 16, wherein the first stimulus is emitted from about 0.1 to about1 second after the detection of the negative peak in said brain activitysignal.
 20. The non-invasive method according to claim 16, furthercomprising emitting same stimuli during a memory training or a learningprocess while said subject is awake.
 21. The non-invasive methodaccording to claim 16, wherein said method is controlled by saidsubject.
 22. The non-invasive method according to claim 16, wherein saidmethod is controlled by a skilled physician.
 23. The non-invasive methodaccording to claim 16, wherein said subject is a healthy subject whichundergoes normal aging or a training period.
 24. The non-invasive methodaccording to claim 16, wherein said subject is affected by amemory-related disorder or a cognitive-related disorder.
 25. Thenon-invasive method according to claim 16, wherein said subject isaffected by a neuronal connectivity disorder.
 26. A device forimplementing a non-invasive method for monitoring a subject's brainactivity and emitting stimuli according to said subject's brainactivity, comprising: a. a monitoring device for measuring saidsubject's brain activity; b. a stimulation device providing at least onetype of stimulus; and c. a programmable microcontroller board configuredto perform the steps of: I. receiving a brain activity signal measuredby said monitoring device; II. monitoring said brain activity signal;III. detecting in said brain activity signal the end of a stage I of anon-REM light sleep state by detection of a negative peak with anamplitude inferior to −75 μV and an onset of stage II of a non-REM lightsleep state; IV. causing the stimulation device to emit a first stimulusat the detection of the onset of stage II of a non-REM light sleepstate; V. causing the stimulation device to emit a second stimulus; VI.causing the stimulation device to repeat the emission of the firststimulus and the second stimulus until an end of stage IV of a non-REMlight sleep state; and VII. repeating steps IV to VII when the onset ofstage II of a non-REM light sleep state is detected.
 27. The deviceaccording to claim 26, wherein said stimulus is a sensory, electricaland/or magnetic stimulus.
 28. The device according to claim 26, whereinboth stimuli are separated by a time interval comprised between 0.5second to 2.5 seconds.
 29. The device according to claim 26, wherein thefirst stimulus is applied from about 0.1 to about 1 second after thedetection of a negative peak in said brain activity signal.
 30. Thedevice according to claim 26, further comprising the application of samestimuli during a memory training or a learning process while saidsubject is awake.
 31. The device according to claim 26, furthercomprising a communication module.
 32. The device according to claim 26,wherein said device is controlled by the subject.
 33. The deviceaccording to claim 26, wherein said device is controlled by a skilledphysician.
 34. The device according to claim 26, wherein theprogrammable microcontroller board is further configured to perform astep of filtering said brain activity signal.
 35. The device accordingto claim 26, further comprising a computer-readable storage medium. 36.The device according to claim 26, further comprising a user interface.37. The device according to claim 26, wherein the user interface isconfigured to visualize physiological parameters of the subject.